Purpose: This phase I study was designed to determine the bioequivalence of a tablet combining the chemotherapeutic agent 776C85/5-FU to the individual 776C85 and 5-FU tablets. Advantages of a combination tablet include a reduction in the chance that a patient would receive 776C85 and a standard dose of FU, which could result in a fatal toxicity. It makes it easier for patients to take the medication, and it ensures that patients do not take oral 5-FU without 776C85. In preclinical and early clinical studies, 776C85 significantly increased the bioavailability and half-life of oral 5-FU, and reduced the pharmacokinetic variability of oral 5-FU. It also increased the antitumor efficacy of 5-FU and increased the therapeutic index of 5-FU up to six-fold in rodent tumor models. Methods: This was a randomized, open-label 3-way crossover study in 36 patients comparing individual 5-FU and 776C85 tablets to each strength of the combination of 775C85 and 5-FU tablet. Each subject was randomly assigned to one of six treatment sequences and received one of three treatments during each study period and all three treatments during the study. Each period consisted of two days of dosing and a five-day washout. 776C85 (20 mg) was administered as a single agent twice daily on day 1 and as a single evening dose on day 2 of each period. All patients received a 2.0 mg dose of 5-FU and a 20 mg dose of 776C85 on the morning of day 2. Serial blood samples were collected following each dose of 5-FU to measure plasma 5-FU, 776C85, and uracil concentrations. Results: This study was closed to accrual on 4/20/98. The study met its accrual goal. A total of 11 Duke patients were enrolled. All of the patients completed this phase I study and continued to receive drug under a separate open-label study. There were no reportable adverse events. Overall, patients appeared to have improvement in their quality of life with decreased symptoms and stabilization of disease. Future plans: Based on the results of this trial, the combination tablet will be used in further studies.